Keratin exfoliative compositions



Patented Oct. 21, 1952 2,614,963 KERATIN ,EXFQLIATIVE coiurosrrloNs William 0. Elson, Chicago, 111., assignor to The Kendall Company, Boston, Mass., a' corporation of Massachusetts No Drawing. Application January .10, 1951, Serial No. 205x135 This invention relates to the treatment of the skin and specifically relates to compositions of matter useful in the treatment and/or the removal or other eliminationof calluses,corns and other undesirable keratin and keratinaceous matnovel keratin exfoliating agents mixed withcarriers of the type hereinafter described and provide keratin exfcliative activity equal, and in some instances superior, to that obtained by presentday salicylic acid compositions in the treatment of corns and the like. Many compositionsof this invention have been found to produce more nearly complete keratin exfoliation and with reduction in the time necessary for treatment.

Compositions of this invention comprise an admixture of a substantially non-volatile organic film-forming vehicle with an acid which falls Within the group of organic acids having acid factors, as hereinafter defined, within the narrow range of 1.5 to 3.5, and lipoid coefiicients, as hereinafter defined, not greater than 5, other than salicylic acid.

. The acid factor of a substance is defined, for the purposes of this invention, as the pH of a saturated water solution of a substance at 37 C. Originally hot and cold solutionsare agitated at 37 C., for 24 hours, the pH of each is then determined by usual methods, and the two pHs are averaged.

The lipoid coefficient of a substance is defined for the purpose of this invention as the ratio at 37 C. of the solubility of the substance in water to the solubility of the substance inbenzene. To

determine the lipoid coefficient, excess amounts of the compound are placed in two pairs of flasks containing respectively hot and cold distilled water and hot and cold CP benzene. The flasks are then agitated at 37 C. for 24 hours to obtain completely saturated solutions in the two liquids. Exactly 20. cc. each of the.. Oursaturated, solutions are heat dried in weighingbottles at approximately 50 C. until no liquid remains. They are then further dried at approximately 100 C., until constant weight is obtained. The residuecontaining bottles'are cooled in a desiccator and weighed. The gain in weight of the respective bottles represents the weight of dried material 21 claims (01. 167 61) soluble in equal volumes of water and-benzene respectively.

Lipoid coeflicient K:

.. mgm./20 cc. water solution at 37 C.

mgm./20 cc. benzene solution at 37 C.

The average residue in 20 cc. from originally hot and. cold solutions is used in the above formula. r

As an alternative method, after obtaining completely saturated solutions, exactly 20 cc. of each of thefour saturated solutions are pipetted into clean 250 cc. flasks. These are dilutedwith 5i! cc. of ethyl alcohol and titrated with standardized T 6 N alcoholic potassium hydroxide with phenolphthalein as the indicator. The milligrams of acid per 20 cc. are calculated by the usual method whereuponthe lipoid coefficient is determined as above.

So far as I am aware, I am the first to discover not only; that these two apparently unrelated physico-chemical properties are of controlling significance'in the determination of keratin exfoliative activity but that when, both the acid factor and lipoid coefiicient of an acid fall within limited narrow ranges, it can be counted upon, when included as the active ingredient of compositions of this invention, to provide sufiicient keratin exfoliative activity for successful keratin exfoliation, just as salicylic acid can be so counted upon, since ,it has both acid factor and lipoid coeiiicient in the proper ranges.

Notonly is each of these properties important but both ;are essential since clinically acceptable keratin exfoliative activity is found only in substances simultaneously possessing both of these properties. .In my experience, those substances possessing both properties have always produced satisfactory clinical keratin exfoliation, while those substances possessing one but lacking the other, as well as those lacking both, have not produced satisfactory clinical keratin exfoliation.

Because ofjthe requirements simultaneously of a definite, narrow lipoid coefficient range and a specific, narrow acid factor range, the field of keratin exfoliating agents is now distinctly segregated, and viewed from the standpoint of rare g Among substances having proper acid factor and lipoid coefficient values and hence acceptable keratin exfoliative activity are aromatic ethers and thioethers of aliphatic acids including the entire group of alpha linked phenoxy and phenylmercapto aliphatic acids having less than six carbon atomsi in each of one or more aliphatic acid radicals. and with or without one on more. halogen or alkyL. (below pentyl) groups replacing up to not more than 3 of the hydrogens of the phenyl radical, examples of which are:

Structural Formula" Name Lipoid g g gi O-CHzC 0 OH plmnoxyethanoic acid 0. 4 2. 1

S-CHaO 0 0E phenylmercaptoethanoic acid; 0.05 2. 4

CH3 2-phenoxypr0panoicac1dl"-06.. v 0.06. 2; A O-(JH C O OH GaHu- 2-plienoxyhutanloic'acid 0; 01' 2. 4

O-OH5C O'O'H 2-c'h1orophenoxyethanolc acid 0.4 2.8

o-v-cmo'o'on Lchlorbphenoxyethanoic acid o. 4 2; 7

0-0 H: 0'0 0H 2,4-dichlorophenoxyeth anoic acid. 0. 06 2. 8

0:111 I z-phencxypentanoicaeii 0.01 2. 9

O:- H (1010B O-QmQ-QOH 2,4,Etririflorbphenoxyethanoicacid. 0; 5 s. s

O-GHaCTOOH i-trt-butylphenoxyethanoic mm.-. 0. 0i 3; 0

mam-m Other phenoxy and phenylmercapto aliphatic acids which have iipoid ccefiicients and acid factors within the required range are 2-pheny1mercaptcpropanoic acid, 2-pheny1mercaptobutanoic acid, 2-pheny1mercaptopentanoic acid, 3-phencxypropanoic acid, 3-pheny1mercaptopropanoic acid, 2-chlorophenylmercaptoethanoic acid, 4- chlorophenylmercaptoethanoic acid, 2,4-dich1orophenylmercaptoethanoic acid, 2,4,5 trichlorophenylmercaptoethanoic acid, 2-methy1phenylmercaptoethanoic acid, 4-methy1pheny1mercaptoethanoic acid, 4-t-butylphenylmercaptoethanoic acid, 2,5--dimethylphenyhilercaptoethania'ic acid,

phenylene-di-mercaptcethanoic acid, diphenylmercaptoethanoic acid, 2,3 diphenylmercabtobutanedioic acid, o-methoxyphenoxyethanoic acid, o-ethoxyphnoxyethanoic acid, c-methoxyphencaptoethanoic acid.

Another group. of suitable substances are phthalic nan esters such as methyl-acid phthal- 3,4-dimethylphenyimercaptoethanoic acid, 1,4-

ylmercaptoethanoic acid and o-ethoxyphenfilmer- Another group of substances possessing the significant properties are benzoic acid derivatives such as Z-methoxybenzoic acid, Z-ni'ethylbenzoic acid, 2-fiuorobenzoic acid and thio'salicylic acid.

The number of carbon atoms in all of the above substances is more than seven whenever the number of non-cyclic oxygen atoms is exactly three.

Other cyclic compounds in the proper ranges are heterocyclic, examples being thiophene-Z- carboxylic acid, 2-furoic acid and Z-furalpropenic acid.

The best agents have lipoid coemcients of .4 to .001 and acid factors of about 2.1 to 2.5.

An illustration of how certain only of a number of closely related acids are useful is afforded by an examination of homologous series of compounds.

As revealed in Table I, phthalic acid has an acid factor in the proper range but the lipoid coefficient is outside the range. It has no appreciable keratin exfoliative activity. Surprisingly, methyl acid phthalate, which differs structurally only by the replacement of the hydrogen of one of the carboxy groups by a methyl group, has such increased water solubility and benzene solubility that it falls within the proper range with respect to both acid factor and lipoid coefiicient. .It: will be noted that. the significant factors are in the proper ranges, butthey are are not at optimum values, so optimum clinical results would not be expected.

Next, n-propyl acid phthalate, which involves only thereplacementof the methyl by a propyl group, has near optimum values for acid factor and lipoid coefficient and has excellent clinical activity.

Next, n-butyl acid phthalate, involving replacing propyl by a butyl group carries the acid factor beyond the optimum but'still in the range. This compound is clinically better than the methyl homolog but not 'so good as the propyl homolog.

Structural Formula Name Lipoid igg thiophene-2-carboxylic acidv 0. l 2. 6

OOOH s I '2furoicacid..;. 1; i;. QQ 3.5 1.9

'COOH 2-futa1propenio acid Still another group of suitable substances are .aliphatic acids such as di-n-butylmalonic acid,

di npropy1malonic acid and 2-butenoic acid Higher homologs move further away from the optimum until they are finally outside the acid factor range.

Table I r Elicia Clinical Structure Name Llpold pFactor Activity Phthalic mam, 44. 2.3 mm. 0001:

coon

' Methyl acid l .24 2.0 rm.

00011 phthalate; 1 i

COOCH:

nPropyl acid 2.4 Excellent. 0 OH phthalate.

n' Butyl acid 2.9 Verygood. coon phthalateam a v v y oooonzomonzoin Compositions of this inve i on may contain, in addition to th min-farming vehicle and the keratin exfoliating acid, other ingredients such as inert diluents and fillers, I I The film-formingvehiclemay be asilicone conforming with the structuraliorrnula;

where R, is a hydrocarbonradical,

Preferably silicones havingviscosities, in excess 01110 centistokes and up to ,lll centistokes are useful. The preferred silicones ,are the lower alkyl silicones such as methyl, butyl andamyl but aryl silicones suchasi-benzyl, silicone, and alkyl aryl silicones suchas 'methylphenyl sili-t cone, may beused. u

rWhere the vehicle is a silicone, the proportions for corn and callus treatment preferably lie with in the ranges by weight, from 2% to 80% agent, from 0% to 78% filler,fand from %,,130 70% silicone. Whenever the preparationis to be used fonkeratin exfoliation on portions ,of the body, other than the foot, however, compositionscontaining silicone in amounts as high, as 99.5% by weight may be utilizedto advantage. 1 i Where preparationsof this invention usefilm forming vehicles of plastioized rubberjor petro latumor other popular films-forming vehicles for. salicylic acid suchlas lanolin, collodion',,oils and waxes and ethylene glycol, methylene glycol, pro

positions of such consistency are most suitable for mounting on fibrous or non-fibrous backing materials, e. g., in theiforni of small slices cut from extruded slugs assembled with shaped cushioning materials-on adhesive backin strips to formcorn and callus treatment units in known manners. For this purpose I find silicone vehicles particularly useful, with ,plasticized rubber and petrolatum being next preferred vehicles in that order'f Certain film-forming vehicles should or can' be carried in a volatile diluent, for example an alcohol, ether, or 'keton common examples being collodion, or Tether volatile diluent carried film-forming cellulosederivatives, or vinyl polymers or co-polymersc Any of the vehicles may be modified with compatible plasticizers or softeners.

The film-formingvehiclespf compositions of thisv invention are preferably, like those above named, non-toxic to the skin in the absence of the active ingredient or ingredients of the compo sition and, as is obvious, should be of such pH and non-reactivity (or limited reactivity) towards the agent as to insure the presence in the composition of sufiicientfree keratinexfoliating acid, when the agent is usedin the proportions herein specified, to permit-gradual-release of the acid from the vehicle after the composition has been appliedto the skin. o r v 1;

Salve-like preparations of this invention with silicone or ointment bases may be preferredby l some for'all exfoliative purposes but theyare pylene glycol and polyethylene glycol"'(known to t the trade as Carbowaxlf the percentageyby weight of the exfoliating agentim'ay, in general,

be 045% and up, of the'total'compositionyanyf given percentage being dictatedfforthe"most part, by the, condition treated andthe degree of exfoliating desired. Percentages of exfoliative agent in excess of 40% have not beenfound appreciably to increase the effectiveness of compositions. For maximum exfoliation, therefore, any higher percentage consistent, with the desired physical characteristics of the composition *may be used, it being understood thatadditionalagentl decreases the plasticity and cohesivenessof the composition.

For corn and callus treatment, I preter that; the compositions have adoughy consistency be ause of thei reduced tenden t best suited for application to portions of the skin surface not subject to the preSsure, friction and temperatures usually associated with foot applications, W. m

Compositions of -this invention comprising the vehicle and the exfoliating agentand with or without fillers may vary from very light quick drying or non-drying liquid solutions and dispersions of film-forming materials and agents to substantially non-drying salve-like compositions ranging in viscosity froin*l0 fup through and above 10 centistokes at F. andincluding on upto doughy oonformable-semi-solid compositions, the viscosities, of which are too high for easy centistoke determination but which have plasticities from 30 to atAOf on the Williams Plastometer; Viscositiejs'andplasticities within this range i nay be [controlled ive proportions of the 'vehiclejtand C. as measuredor other water-swellable materials such as kaolin,

wood flour, talc, zein and clays such as bentonite.

Water-soluble fillers can be, for example, gum arabic or sodium carboxymethylcellulose. Useful relatively water-insoluble fillers include magnesium silicate, aluminum silicate, calcium silicate, sulfur, diatomaceous earth and asbestos.

If it is desirable, a local anesthetic may be added to the preparations of this invention without changing their general physical properties or keratin exfoliative activity appreciably. For instance, that anesthetic popularly known as dibucaine or percaine and which has the chemical name butyioxy-cinchoninic acid diethyl-ethylene diamine hydrochloride may be added, preferably to about 1% of the total weight of the other ingredients.

As illustrative of the compositions of the invention suitable for various keratin exfoliative purposes the following are given, percentages by Example 1 l wkExample I Per cent Thiophene-Z-carboxylic acid 10 Stearyl alcohol 9 Liquid petrolatum 9 Water 9 Petrolatum light 63 Example 11 Per cent Di-n-butylmalonic acid Talc 20 Petrolatum 40 Zinc oxide 20 Example 12 Per cent Phenylmercaptoethanoic acid 32 Oil of cade 20 Castor oil 16 Ethyl alcohol 32 Example 13 Per cent 2-butenoic acid 8 Polyethylene glycol (Carbowax 1580) 92 I Ea'ample14 Per cent Diphenoxyethanoic acid 40 Silicone-(methyl silicone 1,000 centistokes) Starch i V Per cent Phenoxyethanoicacid 20 Collodion 80 I r H Per cent Phenoxyethanoic acid 40 Silicone (methylsilicone, 30,000 centistokes) 30 'Emam'ple4 Y Per cent Phenylmercaptoethanoic acid 30 Lanolin i Percent Z-phenoxypropanoic acid 20 Lanolin 14 White wax. 4 White petrolatum l;e 62

Percent 2-chlorophenoxyeth'a'noic acid .5 White 'petrolatum" 99.

,E m ef ..Percent Z-fiuorobenzoic acid 25 Lanolin 30 White petrolatum 45 Emample8 '5 I Per cent, n-Butyl acid phthalate -39 Aquaphor, Duke Lab.: v

OXycholesterol 3.6 Petrolatum 57.4

Example 9 i v ,Per cent 2-methylbenzoic acid i 15 Hydrosorb, Abbott'Laborat'ories' {fatty acid ester of diethanolamine mixed with petro-' Compositions containing some of the phenoxy and phenylmercapto aliphatic acids herein described are disclosed in my copending application Serial No. 205,436, filed January 10, 1951.

It should be understood that I do not regard the invention hereof as limited other than by the claims to compositions containing an particular keratin exfoliating agent.

I I claim:

1. A keratin exfoliative composition comprising an admixture of a substantially non-volatile non-toxic viscous organic film-forming vehicle and, as an active exfoliating agent, an organic acid selected from the group consisting of aromatic acids having more than 7 carbon atoms, heterocyclic acids and mono and di-carboxylic aliphatic acids, which have acid factors of from 1.5 to 3.5 and lipoidcoefiicients not greater than 5,' s'aid agent being'include d in said composition in an amount providing as free acid from 0.5 to by weight based upon the total weight of the non-volatile ingredients of said composition.

2. A keratin exfoliative composition as claimed in claim 1, wherein the organic acid is an arcmatic acid having more than 7 carbon atoms and an acid factor of from 1.5 to 3.5 and a lipoid coefficient not greater than 5.

3. A keratin exfoliative composition as claimed in claim 2, wherein the aromatic acid is an ether linked aryl acid.

4. A keratin exfoliative composition as claimed in claim 2, wherein the aromatic acid is a phenoxy aliphatic acid.

5. A keratin exfoliative composition as claimed in claim 2, wherein the aromatic acid is a phenylmercapto aliphatic acid.

6. A keratin exfoliative composition as claimed inclaim 2, whereinthe aromatic acid is a phthalic acid half .ester.

7. A keratin exfoliative composition as claimed in claim 1, wherein the organic film-forming vehicle is plasticized rubber.

8. A keratin exfoliative composition as claimed in claim'l, wherein the organic acid has an acid 13 factor of from about 2.1 to 2.5 and a lipoid coefficient of 0.001 to 0.4.

9. A keratin exfoliative composition comprising an admixture of a substantially non-volatile non-toxic organic film-forming vehicle, a volatile liquid organic diluent for said vehicle, and, as an active exfoliating agent, an organic acid selected from the group consisting of aromatic acid-s having more than 7 carbon atoms, heterocyclic acids and monoand di-carboxylic aliphatic acids, which have acid factors of from 1.5 to 3.5 and lipoid coefiicients not greater than 5, said agent being included in said composition in an amount providing as free acid from 0.5 to 80% by weight based upon the total weight of the non-volatile ingredients of said composition and said composition having a viscosity less than 160 plasticity at 40 C. as measured on a Williams Plastometer.

10. A pharmaceutical product for corn and callus treatment comprising an adhesive backing strip bearing a shaped cushioning material and a composition of doughy coformable semi-solid consistency, said composition comprising an admixture of a substantially non-volatile non-toxic viscous organic film-forming vehicle, a finely divided inert filler, and, as an active exfoliating agent, an organic acid selected from the group consisting of aromatic acids having more than 7 carbon atoms, heterocyclic acids and monoand di-carboxylic aliphatic acids, which have acid factors of from 1.5 to 3.5 and lipoid coefficients not greater than 5, said agent being included in said composition in an amount providing as free acid from 05 to 80% by weight based upon the total weight of the non-volatile ingredients of said composition.

11. A keratin exfoliative composition comprising an admixture of a substantially non-volatile non-toxic viscous organic film-forming vehicle, and, as an active exfoliating agent, phenoxyethanoic acid in an amount providing as free acid from 0.5 to 80% by Weight based upon the total weight of the non-volatile ingredients of said composition.

12. A keratin exfoliative composition comprising an admixture of plasticized rubber and, as an active exfoliating agent, phenoxyethanoic acid in an amount providing as free acid from 0.5 to

80% by weight based upon the total weight of the non-volatile. ingredients of said compositionplasticity as measured on a Williams Plastometer.

14. A pharmaceutical product for corn and callus treatment comprising an adhesive backing strip bearing a shaped cushioning material and a composition of doughy conformable semi-solid consistency, said composition comprising an ad-.

mixture of a substantially non-volatile non-toxic viscous organic film-forming vehicle, and, as an active exfoliating agent, phenoxyethanoic acid in an amonut providing as free acid from 0.5 to

1 '14 by weight based upon the total Weight of the non-volatile ingredients of said composition.

15. A keratin exfoliative composition comprising an admixture of a substantially non-volatile non-toxic viscous organic film-forming vehicle, and, as an activeexfoliating agent, phenylmercaptoethanoic acid in an amount providing as free acid from 0.5 to 80% by weight based upon the total weight of the non-volatile ingredients of said composition. 1

16. A keratin exfoliative composition comprising an admixture of a substantially non-volatile non-toxic viscous organic film-forming vehicle,

and, as an active exfoliating agent, Z-phenoxybutanoic acid: in an amount providing as free acid from 0.5 to 80% by weight based upon the total weight of the non-volatile ingredients of 1 ing an admixture of a substantially non-volatile non-toxic viscous organic film-forming vehicle,

and, as an active exfoliating agent, thiophene-2- carboxylic acid in an amount providing as free acid from 0.5 to 80% by weight based upon the total weight of the non-volatile ingredients ofsaid composition.

20. A keratin exfoliative composition as claimed in claim 1, wherein the organic acid is a di-carboxylic acid having more than 7 carbon atoms and an acid factor of from 1.5 to 3.5 and a lipoid coefficient not greater than 5.

21. A keratin exfoliative composition as claimed in claim 1, wherein the organicacid is a mono-carboxylic acid having more than '7 carbon atoms and an acid factor of from 1.5 to 3.5 and a lipoid coefficient not greater than 5.

WILLIAM O; ELSON.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,299,604 Weirich Oct. 20, 1942 2,347,983 Backoif May 2, 1944 FOREIGN PATENTS Number Country Date 725,945 Germany Oct. 2, 1942 OTHER REFERENCES Barondes: The Military Surgeon, May 1950, volume 106, Number 5, pages 379, 3.83 to 387.

Goodman: Cosmetic Dermatology, McGraw- Fill 3001; Company, New York, 1936, pages 454: 

1. A KERATIN EXFOLIATIVE COMPOSITION COMPRISING AN ADMIXTURE OF A SUBSTANTIALLY NON-VOLATILE NON-TOXIC VISCOUS ORGANIC FILM-FORMING VEHICLE AND AS AN ACTIVE EXFOLIATING AGENT, AN ORGANIC ACID SELECTED FROM THE GROUP CONSISTING OF AROMATIC ACIDS HAVING MORE THAN 7 CARBON ATOMS, HETEROCYCLIC ACIDS AND MONO-AND DI-CARBOXYLIC ALIPHATIC ACIDS, WHICH HAVE ACID FACTORS OF FROM 1.5 TO 3.5 AND LIPOID COEFFICIENTS NOT GREATER THAN 5, SAID AGENT BEING INCLUDED IN SAID COMPOSITION IN AN AMOUNT PROVIDING AS FREE ACID FROM 0.5 TO 80% BY WEIGHT BASED UPON THE TOTAL WEIGHT OF THE NON-VOLATILE INGREDIENTS OF SAID COMPOSITION. 